20 Août 2011

Tissue Microarray Cytometry Reveals Positive Impact of Homeodomain Interacting Protein Kinase 2 in Colon Cancer Survival Irrespective of p53 Function

Source: Web site Fluofarma

Isabelle Soubeyran(a), Isabelle Mahouche(a), Aude Grigoletto(a), Thierry Leste-Lasserre(b), Guillaume Drutel(b), Christophe Rey(a), Stephane Pedeboscq(a), France Blanchard(a), Veronique Brouste(c), Jean-Christophe Sabourin(c), Josy Reiffers(a), François Ichas(a,d) and Francesca De Giorgi(a,d)

(a) INSERM U916, Institut Bergonié, 229 cours de l’Argonne, 33076 Bordeaux, France

(b) INSERM U862, Institut François Magendie, 146 rue Léo Saignat, 33077 Bordeaux, France

(c) INSERM U614, Faculté de Médecine, Institut de Recherche Biomédicale, 22 Boulevard Gambetta 76183 Rouen , France

(d) Fluofarma, 2 rue Robert Escarpit, 33600 Pessac, France

The human p53 gene is a tumor suppressor mutated in half of colon cancers. Although p53 function appears important for proliferation arrest and apoptosis induced by cancer therapeutics, the prognostic significance of p53 mutations remains elusive. This suggests that p53 function is modulated at a posttranslational level and that dysfunctions affecting its modulators can have a prognostic impact. Among p53 modulators, homeodomain interacting protein kinase (HIPK) 2 emerges as a candidate “switch” governing p53 transition from a cytostatic to a proapoptotic function. Thus, we investigated the possible prognostic role of HIPK2 on a retrospective series of 80 colon cancer cases by setting up a multiplexed cytometric approach capable of exploring correlative protein expression at the single tumor cell level on TMA. Crossing the data with quantitative PCR and p53 gene sequencing and p53 functional assays, we observed the following: despite a strong impact on p21 transcription, the presence of disabling p53 mutations has no prognostic value, and the increased expression of the HIPK2 protein in tumor cells compared with paired normal tissue cells has a strong impact on survival. Unexpectedly, HIPK2 effect does not appear to be mediated by p53 function because it is also observed in p53-disabling mutated backgrounds. Thus, our results point to a prominent and p53-independent role of HIPK2 in colon cancer survival.

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